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The Road Less Traveled: Perspectives on an Effective HIV Vaccine
Larry Corey, MDPrincipal Investigator, NIAID supported HIV Vaccine Trials Network (HVTN)
Past President and Director, Fred Hutchinson Cancer Research Center Professor, Laboratory Medicine and Medicine, University of Washington
Seattle, Washington USA
Global estimates for adults and children 2017
People living with HIV 36.9 million [31.1 million–43.9 million]
New HIV infections in 2017 1.8 million [1.4 million–2.4 million]
AIDS-related deaths in 2017 940 000 [670 000–1.3 million]
About 5000 new HIV infections (adults and children) a day 2017
About 66% are in sub-Saharan Africa
About 500 are among children under 15 years of age
About 4400 are among adults aged 15 years and older, of whom:─ almost 43% are among women
─ about 33% are among young people (15–24)
─ about 19% are among young women (15–24)
Adults and children newly infected with HIV 1990–2017
Adults and children newly infected with HIV
Range of uncertainty
Adult and child deaths due to AIDS 1990–2017
Adult and child deaths due to AIDS
Range of uncertainty
Indiana HIV Outbreak: Geographic DistributionScott County pop. 24,000; Austin, IN pop. 4,200
Scott County Adams, NEJM 2015;373:1379-1380
The Need for an HIV Vaccine
• With asymptomatic acquisition, prolonged subclinical infection, and sexual transmission, getting to an AIDS Free Generation will require a biologically based primary prevention modality with prolonged durability; preferably an effective HIV vaccine.
• Larry’s definition of an AIDS Free Generation; 95% reduction in incident cases annually: o USA < 2,500 cases yearlyo Globally < 100,000 cases yearly
1/4/2019 9
Why Has It Been So Hard to Develop an HIV Vaccine?
• Science issues: o Genetic diversity of the virus is greater than any other
pathogeno Envelope is less immunogenic than any other virus envelope
protein; perhaps because of its’ glycan shieldo The gp160 envelope trimeric structure is unique, hard to
simulate and there are fewer trimers on the surface than most viruses
o Animal models are expensive and non-predictive of vaccine efficacy
o There are no human cures of HIV and hence there are no models to mimic (0 of 65 million and counting)
1/4/2019 10
Current Status of HIV Vaccines
• Robust pipeline of new concept immunogens dedicated to eliciting neutralizing antibodies to the virus.
• Major progress in prime boost regimens that elicit non-neutralizing antibodies that appear to be of enhanced magnitude as compared to the RV144 trial and/or equal the immune responses among NHP who are protected in mucosal challenge studies with SHIV.
1/4/2019 11
Current Phase 2B/3 HIV Vaccine Efficacy Trials
AMP (POC)HVTN 703/704
Uhambo(Phase 2B/3)
HVTN 702
Imbokodo(Phase 2B POC)
HVTN 705
RV144: ALVAC prime, gp120 boost Vaccine Efficacy (31%)
0 1 2 12Months 3 6 9
Gag, Pol, Env gp120
ALVAC
vaccine
placebo2009
RV144 – Immune Correlates
Subramaniam PloS Pathogens (2009)
Antibodies to V1V2 region were associated with a reduced risk of infection
Non-neutralizing antibodies
How did the vaccine prevent infection?
Haynes, Kim et al. NEJM (2012)Rolland, Kim at al. Nature (2012)Liao, Haynes et al, Immunity (2013)
Transmission Bottleneck
MucosalSurface
Transmitted Founder
Virus
Cell Killing(ADCC)
Vaccine Induced Antibodies (RV144)
• Non-neutralizing• Kill infected cells• Eradicate initial nidus of infection
Correlation Between Antibodies to the V1V2 Loop and Vaccine Efficacy in RV144
• Antibodies to the conserved region of V2, previously almost completely ignored by the HIV vaccine field, were highly correlated with efficacy.
2010 Formation of the P5 Partnership
Purpose:To build on RV144 data and ultimately license a pox-protein based HIV vaccine with the potential for broad and timely public health impact.
Strategy:• Developed a partnership to
extend the RV144 concept to Clade C regions of the world.
• Use expert committees to select the strains and then use company expertise to manufacture these vaccines for immunogenicity, safety and efficacy.
Build on RV144 design
Optimize regimen for regional relevance (C clade) and increased potency (MF59)
• ALVAC-HIV (vCP2438) expresses • env gp120 of ZM96 strain (subtype C) +
gp41 transmembrane sequence (subtype B LAI strain)
• gag + protease (subtype B LAI strain)• Bivalent Subtype C gp120/MF59:
• env gp120 of TV1.C strain (subtype C)• env gp120 of 1086.C strain (subtype C)• mixed with MF59 adjuvant
HVTN 702
A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 in preventing HIV-1 infection in adults in South Africa
Commenced: Nov. 1, 2016 Chair: Glenda Gray Co-Chairs:
Linda Gail Bekker, Fatima Laher, Mookho Malahlela
First HVTN 702 Vaccination: Soweto-Bara (Oct 2016)
HVTN 702 Schema: 5400 South Africans (18-35 yrs)
Group N*Primary vaccine regimen Boosters
Month 0 Month 1 Month 3 Month 6 Month 12 Month 18
1 2700ALVAC-HIV (vCP2438)
ALVAC-HIV (vCP2438)
ALVAC-HIV (vCP2438) +
Bivalent Subtype C
gp120/MF59
ALVAC-HIV (vCP2438)+
Bivalent Subtype C
gp120/MF59
ALVAC-HIV (vCP2438) +
Bivalent Subtype C
gp120/MF59
ALVAC-HIV (vCP2438) +
Bivalent Subtype C
gp120/MF59
2 2700 Placebo Placebo Placebo + Placebo
Placebo + Placebo
Placebo + Placebo
Placebo + Placebo
Total 5400
Immune Correlates – Phase 2b
HVTN 702: opened in Oct. 2016ALVAC prime, gp120 boost
HrAd26 prime, gp140 boostVTN 705: opened in Nov. 2017
22
APPROACH (Ph 2): Mixture of 4 mosaic Ad26 constructs + gp140 Clade C boost
Prime Boost
0 3 12months 6
Regimen to be selected after Phase 1/2a
+gp140 Clade C
Soluble trimer gp140 env proteins
Ad26.Mos4.HIVAd26 vectors with Mosaic
gag-pol or env inserts
Ad26.Mos1.Gag-Pol
Ad26.Mos2.Gag-Pol
Ad26.Mos1.Env
Ad26.Mos2S.Env
Ad26.Mos4.HIVgag-pol-env
Ad26.Mos4.HIVgag-pol-env
(clade C-like)
(clade B-like)
23
The Ad26/Ad26+Env HIV vaccine regimen provides substantial protection against SHIVSF162P3 challenges in non-human primates [study designed to mimic APPROACH trial (HIV-V-A004)]
6x IR SHIV challenges
N = 12 per group
0 3 12months 6 18
Per-Exposure Risk Reduction
Full Protection after 6 challenges
Ad26/Ad26+Env 94% 66%
Ad26/MVA+Env 87% 42%
Ad26/Env 84% 33%
24
Study Schema: HVTN 705/Imbokodo
Chairs: Glenda Gray, Co-chairs: Susan Buchbinder, Kathy Mngadi and Frank Tomaka
Non-neutralizing Approaches to HIV Vaccine Design
• Two non-neutralizing strategies are being undertaken:o 1 based upon RV144 correlates data and the other based upon
correlates in NHP challenge experiments. o Both approaches suggest correlates relate to both
binding/functional antibodies (ADCP and ADCC), as well as some T cell response (CD4 envelope and the other ELISPOT data).
o We shall see whether these presumed correlates are shown to be consistent in human efficacy trials.
o We shall see if any NHP challenge studies are predictive of vaccine efficacy.
o In the end it may take both neutralizing and non-neutralizing antibodies to achieve success.
1/4/2019 25
Neutralizing Antibodies for HIV Prevention s
iedtu
Syac
icfEf
P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702)
Multi-clade approach using rAd26/MVA/gp140 trimer(Crucell/Janssen)
Neutralizing antibody approach using VRC01(AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085)
Broadly Reactive Neutralizing Antibodies Discovered since 2009
Viral membrane
V1V2 Glycan
CD4 binding site
Glycan-V3 Supersite
Membrane-proximal external region (MPER)
gp120-gp41 Interface
Image by Stewart-Jones, Doria-Rose, StuckeyAdapted from Stewart-Jones et al Cell 2016 and Pancera et al Nature 2014
• Isolated from HIV-infected individuals
• Penetrate glycan shield• Potently neutralize most strains
of HIV-1
Passive Antibody PreventionPhase IIB Efficacy Studies
Can a passively infused monoclonal antibody prevent HIV-1 infection in high risk adults: MSM in Americas & heterosexual women in sub-Saharan Africa
AMP = Antibody Mediated Prevention
• Placebo controlled trial of VRC01 mAb (IV), given on 8 weekly schedule
• Two cohorts:o 2,400 MSM + TG in North & South America (HVTN 704/HPTN 085)o 1,900 Women in sub-Saharan Africa (HVTN 703/HPTN 081)
• Both trials opened in April/May 2016• 703/081 Accrued September 20, 2018 (End Jan 2021)• 704/085 Accrued October 5, 2018 (End Oct 2020)
Chairs: Lawrence Corey, HVTNMike Cohen, HPTN
Co-chairs: Srilatha EdupugantiNyaradzo Mgodi
Cohorts for the AMP Studies
Cohorts Antibody(VRC01)10mg/kg
Antibody (VRC01)
30mg/kg
Placebo Saline
Total Population
HVTN704/HPTN085: 900MSM & TG persons (Clade B)United States, Peru, Brazil &
900 900 2,700
Switzerland
HVTN703/HPTN081: 634*
Heterosexual women (Clade C)Sub-Saharan Africa – 7 countries
634*
634*
1,900
Total 1,534 1,534 1,534 4,600* Due to the randomization scheme, the numbers of vaccine and control recipients may differ slightly.
Study Schema for the AMP studies
INFUSION SCHEDULE (WEEKS)[A = VRC01 infusion; C = Control infusion]
Treatment:VRC01
N 0 8 16 24 32 40 48 56 64 72 80* 92**
Group 1 10 mg/kg 900
634
A A A A A A A A A A
Group 2 30 mg/kg 900
634
A A A A A A A A A A
Group 3 Control 900
634
C C C C C C C C C C
2700 (1900) for the MSM + TG (WSM) group; (1/3 VRC01 30 mg/kg; 1/3 VRC01 10 mg/kg; 1/3 control
*Week 80: last study visit to evaluate efficacy – primary end point**Week 92: final study visit to evaluate safety and tolerability; co-primary end point
Enrollment and Retention Updates703/081
African Women
1901 enrolled
95% retention
99% adherence
704/085MSM + TG
2710 enrolled
94% retention
100% adherence
33
34
First Generation HIV mAbs in the Clinical Pipeline….
Note that first-generation bNAbs are not yet optimized for potency, breadth, half-life, or low-cost production.
An exciting time to be in vaccine discovery….
THE SCIENCE ISADVANCING THROUGHCLINICAL TRIALS
• Three pivotal HIV vaccine related efficacy trials are underway (AMP/Uhambo/Imbokodo)
• These trials will define if either or both neutralizing and/or non-neutralizing antibodies can be tweaked to provide reasonable vaccine efficacy in high risk regions of the world
SCIENTIFIC ADVANCESARE FUELING VACCINEDISCOVERY
• Antibody isolation and characterization has revolutionized our understanding of the immune response
• Technologic advances allow researchers to understand where antibodies target the virus in unprecedented detail
• Stabilization of the HIV Envtrimer allows for engineering of trimeric mimics
• Have shifted from empiric approaches to hypothesis-driven approaches
• Native-like trimers meant to resemble HIV’s Env spike
• Germline-targeting approaches generated using structure-based vaccine design
NEXT GENERATIONVACCINES ARE ENTERINGTHE CLINIC
Questions remain:
• Do bNAbs protect?• Potency and durability?• HIV variability?• bNAb maturation?
Courtesy of John Mascola
AcknowledgmentsHVTN Lab Program
Julie McElrath, Georgia Tomaras, Nicole Frahm, John Hural,
David Montefiori, Steve DeRosa,Erica Andersen-Nissen, Lynn Morris
USMHRPNelson Michael, Robert O’Connell
Bill and Melinda Gates FoundationEmilio Emini, Nina Russell and team
Sanofi PasteurJim Tartaglia, Sanjay Gurunathan,
Sanjay Phogat
JanssenFrank Tomaka, Maria Pau,
Hanneke Schuitemaker, Paul Stoffels
HVTN Core, SDMC, EMTJim Kublin, Peter Gilbert, Glenda Gray,
Susan Buchbinder, Scott Hammer, Gepi Pantaleo, Shelly Karuna,
Nicole Grunenberg, Carter BentleySite Investigators Study Volunteers
CHAVI IDBart Haynes, Larry Liao and colleagues
DAIDS Vaccine Research ProgramCarl Dieffenbach, Mary Marovich,
Dale Hu, Phil Renzullo, Pat D’Souza, Paul Kitsutani, Mary Allen, Jim Lane,
Mike Pensiero
Collaborators - Africa
• Glenda Gray• Linda Gail-Bekker• Gita Ramjee• Cheryl Louw• Kathy Mngadi• Graeme Meintjes• Craig Innes• Nicole Hunt• Phillip Kotze• Francis Martinson
• Jani Ilesh• Stewart Reid• Leonard Maboko• Maphoshane Nchabeleng• Lungiswa Mtingi• Dumezweni Ntshangase• William Brumskine• Zvavahera Chirenje• Mookho Malahlela• Modulakgotla Sebe
Collaborators - U.S., South America and Europe
• Mark Mulligan• Paul Goepfert• Ray Dolin• Lindsey Baden• Ken Mayer• Richard Novak• Benigno Rodriguez• Spyros Kalams• Scott Hammer
• Beryl Koblin• Ian Frank• Michael Keefer• Susan Buchbinder• Julie McElrath• Gepi Pantaleo• Jorge Sanchez• Martin Casapia• Robinson Cabello
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